5-nitrofuryl nitrones

ABSTRACT

WHEREIN N, R, AND R&#39;&#39; HAVE THE MEANING SET FORTH ABOVE.   HONH~R   WITH AN N-SUBSTITUTED HYDROXYLAMINE OF THE FORMULA   2-(O2N-),5-(R&#39;&#39;-CO-(CH=CH)N-)FURAN   WHERE N IS 0 OR 1; R IS A SUBSTITUTED OR UNSUBSTITUTED ALKYL RADICAL HAVING 1 TO 6 CARBON ATOMS, A SUBSTITUTEED OR UNSUBSTITUTED PHENYL RADICAL, OR A SUBSTITUTED OR UNSUBSTITUTED HETEROCYCLIC RADICAL; AND R&#39;&#39; IS HYROGEN OR AN ALKYL RADICAL OF 1 TO 4 CARBON ATOMS. SUCH NITRONE DERIVATIVES ARE PREPARED BY CONDENSING CARBONYL COMPOUNDS OF THE FORMULA   2-(O2N-),5-(R-N(=O)=C(-R&#39;&#39;)-(CH=CH)N-)FURAN   NITRONE DERIVATIVES HAVING ANTI-MICROBIAL ACTIVITY COMPRISING COMPOUNDS OF THE FORMULA

United States Patent 3,701,773 S-NITROFURYL NITRONES Shinsaku Minami, Yamatokouriyama-shi, Jun-ichi Matsumoto, Osaka, Masanao Shimizu, Kobe, and Yoshiyuki Takase, Amagasaki-shi, Japan, assignors to Dainippon Pharmaceutical Co., Ltd., Osaka, Japan No Drawing. Continuation-impart of application Ser. No. 592,265, Nov. 7, 1966. This application July 23, 1968, Ser. No. 746,749

Claims priority, application Japan, Nov. 6, 1960, 40/68,196; July 27, 1967, 42/48,362 Int. Cl. C07d 5/30 U.S. Cl. 260-240 A 42 Claims ABSTRACT OF THE DISCLOSURE Nitrone derivatives having anti-microbial activity comprising compounds of the formula wherein n is 0 or 1; R is a substituted or unsubstituted alkyl radical having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl radical, or a substituted or unsubstituted heterocyclic radical; and R' is hydrogen or an alkyl radical of 1 to 4 carbon atoms.

Such nitrone derivatives are prepared by condensing carbonyl compounds of the formula OgNl (CH=GH) 110 0 with an N-substituted hydroxylamine of the formula HONHR wherein n, R, and R have the meaning set 'forth above.

This application is a continuation-in-part of copending application Ser. No. 592,265, filed Nov. 7, 1966, now abandoned.

The present invention is directed to novel nitrone derivatives having excellent antimicrobial activity; a method of preparing the same; and medicinal compositions containing the same.

Heretofore, some of the N-substituted (5-nitro-2-furfurylidene) amine compounds have been known as substances having antimicrobial activity. It has been noticed, however, that the antimicrobial activities of many of these compounds are not high enough to be satisfactory.

The principal object of the present invention therefore 3,701,773. Patented Oct. 31, 1972 ice (wherein n is 0 or 1; R is a substituted or unsubstituted alkyl radical having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl radical, or a substituted or unsubstituted heretocyclic radical; and R is hydrogen or an alkyl radical having 1 to 4 carbon atoms).

More particularly, R is selected from members of the group A-X, P-Y and a heterocyclic radical wherein A is an alkyl radical having 1 to 6 carbon atoms; P is a phenyl radical; X is a member selected from hydrogen, an hydroxyl radical, an alkoxy radical having 1 to 4 carbon atoms, a phenyl radical, a halogen atom, an alkoxy carbonyl radical (wherein the alkoxy portion has from 1 to 4 carbon atoms), a carbamoyl radical, a nitro radical, a sulfoxy (HOSO radical, an alkali metal oxy-sulfonyl radical (an M0SO radical wherein M is an alkali metal), a heterocyclic radical or an amine radical of the formula wherein R and R are each members selected from hydrogen, alkyl radicals of 1 to 4 carbon atoms, a phenyl radical and a heterocyclic radical; Y is a member selected from hydrogen, an alkyl radical having 1 to 4 carbon atoms, a halogen atom, an hydroxyl radical, an OM radical (wherein M represents an alkali metal), an alkanoyloxy radical having 1 to 4 carbon atoms, an aroyloxy radical, an alkoxy radical having 1 to 4 carbon atoms, an alkanoyl radical having 1 to 4 carbon atoms, an alkanoylamino radical having 1 to 4 carbon atoms, a carboxyl radical or its alkali metal salt, an alkoxycarbonyl radical having 1 to 4 carbon atoms, a carbamoyl radical which may be substituted by a phenyl radical or an alkyl radical having 1 to 4 carbon atoms, a sulfamoyl radical, a sulfoxyl radical, a cyano radical, or a trifiuoromethyl radical.

Further, the heterocyclic radicals represented above are preferably radicals of 5- or 6-membered compounds which contain in the ring at least one atom O, S or N as the hetero-atom. The heterocyclic-radical may be fused sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, or an organic base, e.g., sodium acetate, pyridine or triethylamine, be added to the reaction system.

The important features of the present invention consist in the discovery that a carbonyl derivative of nitrofuran readily reacts with an N-substituted hydroxylamine to form novel nitrone derivatives and that these novel nitrone derivatives have greater antimicrobial activities when compared with such Schiif bases as known N-substituted nitro-2-furfurylidene) amine derivatives similar in chemical structure to the compounds of the present invention. In addition, the compounds of the present invention are superior to the Schitf bases in their solubilities in water and organic solvents so that they are more advantageous in application for liquid medicines.

The novel compounds of the present invention are remarkably effective against diseases due to micro-organisms such as bacteria, fungi and protozoa. Since they have a strong activity, a relatively small dose is sufiicient, and the toxicity is less than those of known nitrofuran derivatives. They can be applied to human beings and other animals as an internal medicine, external medicine or an injection in the present form, in the form of a solution, or together with an adjuvant, carrier or vehicle. Further, it is to be understood that the compounds of the present invention are widely applicable to the fields of food, agriculture, etc. where the removal or prevention'of increase of micro-organisms is required.

The present invention is further illustrated by the following non-limitative examples:

EXAMPLE 1 To a solution of 5.7 g. of S-nitrofurfural and 3.35 g. of N-methylhydroxylamine hydrochloride in ml. of ethanol was added a solution of 3.28 g. of anhydrous sodium acetate in 4 ml. of water. The mixture was heated for 10 minutes on a steam bath, and cooled. A resulting precipitate was collected by filtration, washed with water, and recrystallized from ethanol to give 5.0 g. of a-(S-nitro-2-furyl)-N-methylnitrone (compound 1) as yellow needles melting at 165166 C.

EXAMPLE 2 (A) To a solution of 5.64 g. of S-nitrofurfural and 3.9 g. of N-ethylhydroxylamine hydrochloride was added dropwise with stirring an aqueous, saturated solution of 3.28 g. of anhydrous sodium acetate. The mixture was heated on a steam-bath for 10 minutes, and then cooled. A resulting precipitate was collected by filtration, washed with water, and recrystallized from ethanol to give 45 g. of a-(5-nitro-2-furyl)-N-ethylnitrone (compound 2) as yellow needles melting at 175-l77 C.

(B) In the absence of sodium acetate, a solution of 5.64 g. of S-nitrofurfural and 3.9 g. of N-ethylhydroxylamine hydrochloride was heated on a steam bath for 10 minutes. Then the reaction mixture was treated as described above. There was obtained 3.0 g. of u-(5-nitro-2-furyl)-N-ethylnitrone. This compound was an infrared spectrum identical with that of the compound described under (A) above and shows no depression of the mixed melting point with that compound.

EXAMPLES 3-4 To a stirred solution of 2.2 g. of N-propylhydroxylamine hydrochloride in 20 ml. of ethanol was added 1.6 g. of anhydrous sodium acetate and then 2.8 g. of S-nitrofurfural. The resulting mixture was allowed to stand with stirring at room temperature for 5 hours. A precipitate, after addition of water, was filtered, washed with water, and then recrystallized from a mixture of ethanol and nhexane to yield 3 g. of u-(5-nitro-2-furyl)-N-propylnitrone (compound 3) as yellow scales melting at 82-83 C.

On the same treatment of S-nitrofurfural, N-isopropylhydroxyamine hydrochloride and anhydrous sodium acetate there was obtained a-(5-nitro-2-furyl)-N-isopropylnitrone (compound 4) as yellow scales melting at 103- 104 C.

EXAMPLE 5 To a stirred solution of 2.1 g. of N-( 1-methyl-2-hydroxyethyl)-hydroxylamine hydrochloride in 10 ml. of ethanol was added 1.6 g. of anhydrous sodium acetate and then 2.8 g. of S-nitrofurfural. The mixture was allowed to stand with stirring at room temperature for 2 hours. After filtration of an insoluble material, the filtrate was concentrated to dryness in reduced pressure and the resulting residue was repeatedly extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and followed by evaporation of chloroform. Recrystallization of the residual solid from ethyl acetate gave 9.1 g. of a-(5-nitro-2-furyl)-N-(l-methyl-2-hydroxyethyl) nitrone (compound 5) as yellow needles melting at 136 C.

EXAMPLES 6-8 Following compounds were also prepared from the given reactants by the same method mentioned under Example 5 From S-nitrofurfural, N (2 hydroxyethyl)hydroxyamine hydrochloride and anhydrous sodium acetate there was obtained a (5 nitro-2-furyl)-N-(2-hydroxyethyl) nitrone (compound 6) as yellow needles melting at 151- 152 C.

From 5 nitrofurfural, N-(Z-hydroxypropyl)hydroxylamine hydrochloride and anhydrous sodium acetate there was obtained a (5-nitro-2-furyl)-N-(2-hydroxypropyl) nitrone (compound 7) as yellow scales melting at 147- From S-nitrofurfural, N [2 hydroxy 1(hydroxymethyl)ethyl] hydroxylamine hydrochloride and sodium acetate there was obtained a-(S-nitrO-Z-furyD-N-[2-hydroxyl-l-(hydroxymethyl)ethyl]nitrone (compound 8) as yellow scales melting at 138139 C.

EXAMPLE 9 To a solution of 4.4 g. of N-phenylhydroxylamine in 10 ml. of ethanol was added 5.7 g. of 5-nitrofurfural and the resulting mixture was allowed to stand at room temperature with occasional shaking. After one hour, during which time yellow crystals precipitated, the resulting crystals were collected by filtration and washed with methanol. Recrystallization of the product from ethanol formed 9.5 g. of u-(5-nitro-2-furyl)-N-phenylnitrone (compound 9) as yellow prisms melting at -181 C.

EXAMPLE 10 To a solution of 1.4 g. of N-(4-methoxyphenyl)hydroxylamine in 20 ml. of ethanol was added dropwise a solution of 1.4 g. of S-nitrofurfural in 5 ml. of ethanol. The mixture was allowed to stand with stirring at room temperature for 30 minutes. An orange solid precipitated during this period was collected by filtration, washed with cold ethanol, and then recrystallized from ethanol to give 1.4 g. of a a-(5-nitro-2-furyl) N (4 methoxyphenyl) nitrone (compound 10) as orange needles melting at 172- 193 C.

EXAMPLES 11-29 Following compounds were further prepared from the given reactants by the same method described in Example 10.

From S-nitrofurfural and N -(3 methoxyphenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(3- methoxyphenyl)nitrone (compound 11) as yellow prisms melting at l61.5-l62.5 C.

From S-nitrofurfural and N (2 methoxyphenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(2- methoxyphenyDnitrone (compound 12) as orange needles melting at 164.5165.5 C.

From S-nitrofurfural and N-(4-ethoxypheny1)hydroxylamine there was obtained a-(5-nitro-2-furyl) N (4- ethoxyphenyl)nitrone (compound 13) as orange needles melting at 153154 C.

From 5-nitro-furfural and N (4 tolyl)hydroxylamine there was obtained a-(S-nitro-Z-furyD-N-(4-tolyl)nitrone (compound 14) as yellow needles melting at 159.5- 160.5 C.

From S-nitrofurfural and N-(3-trifluoromethylphenyl) hydroxylamine there was obtained .ot-(S-IlitIO-Z-fUIYD-N- (3-trifiuoromethylphenyl)nitrone (compound 15) as yellow prisms melting at 142-143 C.

From .S-nitrofurfural and N-(4-chlorophenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(4-chlorophenyl) nitrone (compound 16) as orange needles melting at 165166 C.

From .5 nitrofurfural and 6-(3,4-dichlorophenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(3, 4-dichlorophenyl)nitrone (compound 17) as yellow needles melting at 202204 C.

From S-nitrofurfural and 6 (4-iodophenyl)hydroxylamine there was obtained a-(S-nitro-Z-furyl)-N-(4-iodophenyl)nitrone (compound 18) as yellow needles melting at 187-189 C.

From 5-nitrofurfural and N-(4-carboxyphenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(4-car boxyphenyl)nitrone (compound 19) as yellow needles melting at 238241 C. with decomposition.

From -:5-nitrofurfural and N-3-(carboxyphenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(3-carboxyphenyl)nitrone (compound 20) as yellow needles melting at 218-220 C. with decomposition.

From S-nitrofurfural and N-(2-carboxyphenyl)hydroxylamine there was obtained a-(S-nitro-Z-furyl)-N-(2-carboxyphenyl)nitrone (compound 21) as orange needles melting at 149-151 C. with decomposition.

From S-nitrofurfural and N-(4-methoxycarbonylphenyl)hydroxylamine there was obtained a-(-nitro-2-furyl)- N-(4-methoxycarbonylphenyl)nitrone (compound 22) as yellow needles melting at 176--177 C.

From 5-nitrofurfural and N-(4-carbamoylphenyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(4- carbamoylphenyDnitrone (compound 23) as yellow needles melting at 230232 C. with decomposition.

From S-nitrofurfural and -N-(4-cyanophenyl)hydroxylamine there was obtained u-(S-nitrO-Z-furyl)-N-(4-cyanophenyl)nitrone (compound, 24) as yellow needles melting at 198-199 C.

From S-nitrofurfural and N-(4-sulfamoylphenyl)hydroxylaminethere was obtained ot-(5-nitro-2-furyD-N-(4- sulfamoylphenyDnitrone (compound 25) as yellow needles melting at 210 C. with decomposition.

From S-nitrofurfural and N-(S-benzimidazolylhydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(5-benzimidazolyl)nitrone (compound 26) as orange needles melting at 230 C. with decomposition.

From S-nitrofurfural and N-(S-benzimidazolylhydroxylamine there was obtained u-(S-nitro-Z-furyl)-N-(5-benzimidazolyl)nitrone (compound 26) as orange needles melting at 230 C. with decomposition.

From S-nitrofurfural and N-(4-salicyloy1oxyphenyl)hydroxylamine there 7 was obtained a-(S-nitro-Z-furyD-N- (4-salicyloyloxyphenyl)nitrone (compound 28) as yellow needles melting at 210-212 C. with decomposition.

From S-nitrofurfural and N-(5-benzotriazolyl)hydroxyl) amine there was obtained a-(5-nitro-2-furyl)-N- (5 benzotriazolyl)nitrone (compound 29) as yellow needles melting above 360 C.

EXAMPLE 30 To a suspension of 1.38 g. of -(5-nitro-2-furyl)-N- (4-carboxyphenyl)nitrone in 8 ml. of water was added EXAMPLE 31 To a solution of 1.67 g. of ,8-(5-nitro-2-furyl)acrolein and 1.0 g. of N-methylhydroxylamine hydrochloride in 45 ml. of ethanol was added an aqueous, saturated solution of anhydrous sodium acetate. The mixture was allowed to stand for 30 minutes with occasional shaking, warmed on a steam bath for 20 minutes, and then filtered to remove a resulted sodium chloride. After cooling, the resulted crystals were collected by filtration, washed with water and recrystallized from ethanol to give 1.3 g. of a-[2-(5-nitro-2-furyl)vinyl]-N-methyl-nitrone (compound 31) as reddish orange needles melting at 180-182 C.

EXAMPLE 32 To a solution of 1.53 g. of 3-carboxyphenylhydroxylamine in 50 ml. of ethanol was added, with stirring, 1.67 g. of ,B-(5-nitro-2-furyl) acrolein and 2 ml. of acetic acid. The reaction took place immediately. The mixture was heated on a steam bath for 45 minutes with occasional shaking. After cooling, the resulted solid was collected by filtration and recrystallized from dioxane to give 1.5 g. of a- [2- (5-nitro-2-furyl )vinyl] -N- (3 -carboxyphenyl nitrone (compound 32) as dark orange prisms, beginning to decompose above C. without melting.

EXAMPLEv 33 (A) A mixture of 1.55 g. of 5-nitro-2-furyl methylketone, 1.0 g. of N-methylhydroxylamine hydrochloride and 1.0 g. of pyridine in 20 ml. of ethanol was refluxed for 2v hours on a steam bath. After evaporation of the solvent, the residue was cooled to form orange crystals which were collected by filtration and recrystallized from ethanol to give 1.3 g. of a-methyl-a-(5-nitro-2-furyl)-N-methylnitrone (compound 33) as reddish yellow needles melting at 179-180 C.

(B) A use of 10 ml. of only pyridine, in place of ethanol under (A) above mentioned, as both the solvent and the acceptor of hydrogen chloride and the treatment of the reaction mixture by the same manner resulted again in a formation of 1.4 g. of the identical product with that obtained previously under (A).

EXAMPLES 3 4-3 6 EXAMPLES 37-40 Following compounds were further prepared from the given reactants by the same method as described in Example 5.

From -nitrofurfural and N-(1,1-dimethy1-2-hydroxyethyD-hydroxylamine hydrochloride there was obtained a-(5-nitro-2-furyl) N (1,l-dimethyl-Z-hydroxyethyl) nitrone (compound 37) as yellow needles melting at 135- 137 C.

From S-nitrofurfural and N-(1,1-dihydroxymethyl-2- hydroxyethyl) hydroxylamine hydrochloride there was obtained a-(5-nitro-2-furyl)-N-( 1,1 dihydroxymethyl-Z- hydroxyethyl)nitrone (compound 38) as yellow needles melting at 172-173" C.

From S-nitrofurfural and N-(ethoxycarbonylmethyl) hydroxylamine hydrochloride there was obtained a-(S-nitro-2-furyl) N (ethoxycarbonylmethyhnitrone (compound 39) as yellow needles melting at 114-115 C.

From 5-nitrofurfural and N-(carbamoylmethyl)hydroxylamine hydrochloride there was obtained a-(S-nitro-Z- furyl)-N-(carbamoylmethyl)nitrone (compound 40) as yellow needles melting at 189-191 C.

EXAMPLES 41-45 Following compounds were further prepared from the given reactants by the same method as described in Example 10.

From S-nitrofurfural and N-(2,3-dicarboxyphenyl)hydroxylamine there was obtained a-(S-nitro-Z-furyU-N- (2,3-dicarboxyphenyl)nitrone (compound 41) as yellow needles melting at 225-227 C. with decomposition.

From S-nitrofurfural and N-(6-benzothiazolyl)hydroxylamine there was obtained a-(5-nitro-2-furyD-N-(6- benzothiazolyl)nitrone (compound 42) as orange needles melting at 215-216 C. with decomposition.

From S-nitrofurfural and N-(6-methoxy-8-quinolyl) hydroxylamine there was obtained a-(5-nitro-2-furyl)-N- (6-meth0xy-8-quinolyl)nitrone (compound 43) as yellow needles melting at 204-205 C. with decomposition.

From S-nitrofurfural and N-(l-methyl-Z-nitroethyl)hydroxylamine there was obtained a-(5-nitro-2-furyl)-N-(1- methyl-2-nitroethyl)nitrone (compound 44) as yellow scales melting at 111-1 12 C.

From S-nitrofurfural and N-(2-sodioxysulfonylpropyl) hydroxylamine there was obtained a-(5nitro-2-furyl)-N- (Z-sodioxysrflfonylpropyl)nitrone (compound 45) as yellow powder melting at 200-203" C. with decomposition.

EXAMPLES 46-50 Following compounds were further prepared from the given reactants by the same method as described in Example 31.

From )3-(5-nitro-2-furyl)acrolein and N-(l-hydroxymethylethyl)hydroxylamine hydrochloride there was obtained a-[2-(5-nitro-2-furyl)vinyl] N-(l-hydroxymethylethyl)nitrone (compound 46) as reddish orange needles melting at 182183 C.

From B-(5-nitro-2-furyl)acrolein and N-(Z-hydroxyethyl)hydroxylamine hydrochloride there was obtained a-[2-(5-nitro-2-furyl)viny1] N-(2-hydroxyethyl)nitrone (compound 47) as reddish orange needles melting at 190- 191.5 C. with decomposition.

From fl-(5-nitro-2-furyl)acrolein and N-(1,1-dihydroxymethyl 2-hydroxyethyl)hydroxylamine hydrochloride there was obtained a-[2-(5-nitro-2-furyl)vinyl]-N- (l,1-dihydroxymethyl-Z-hydroxyethyl)nitrone (compound 48) as reddish orange needles melting at 198-199 C.

From )8-(5-nitro-2-furyl)acrolein and N-(2-hydroxypropyl)hydroxylamine hydrochloride there was obtained a-[2-(5-nitro 2 furyl)vinyl] N (2-hydroxypropyl)nitrone (compound 49) as reddish orange scales melting at 171-172 C.

From fl-(5-nitro-2-furyl)acrolein and N-(1,1-dimethyl- 2-hydroxyethyl)hydroxylamine hydrochloride there was obtained u-[Z-(S-nitro 2-furyl)vinyl]-N-(1,1-dimethyl-2- hydroxyethyl)nitrone (compound 50) as reddish orange scales melting at 174-175 C.

10 EXAMPLES 51-54 Following compounds were further prepared from the given reactants by the same method as described in Example 32.

From }8-(5-nitro-2-furyl) acrolein and N-(6-benzothiazolyl)hydroxylamine there was obtained ot-[2-(5-nitro-2- furyl)vinyl]-N-(6-benzothiazolyl)nitrone (compound 51) as red needles melting at 218-219 C. with decomposition From p-(5-nitro-2-furyl)acrolein and N-(4-sulfamoy1- phenyl)hydroxylamine there was obtained a- [2-(5-nitro- 2-furyl)vinyl]-N-(4-sulfamoylphenyl)nitrone (compound 52) as yellow needles melting at ZOO-203 C. with decomposition.

From B-(5-nitro-2-furyl)acrolein and N-(S-benzimidazolyl)hydroxylamine there was obtained u-[2-(5-nitro- 2-furyl)vinyl] N-(5-benzimidazolyl)nitrone (compound 53) as red needles melting at 205 C. with decomposition.

From fl-(S-nitro-Z-furyl)acrolein and N-(6-quinolyl) hydroxylamine there was obtained a-[2-(5-nitro-2-furyl) vinyl]-N-(6-quinolyl) nitrone (compound 54) as red needles melting at ZOO-201 C. with decomposition.

EXAMPLE 55 A solution of 2.12 g. of S-nitrofurfural and 3.04 g. of N-(1,1-dimethyl 2 dimethylaminoethyl)hydroxylamine hydrochloride in 30 ml. of ethanol was stirred for 20 minutes at room temperature. The precipitating crystals were collected by filtration, and dissolved in 3 ml. of water. The solution was made alkaline by adding thereto a saturated aqueous solution of sodium hydrogen carbonate, and the precipitating crystals were collected by filtration, washed with water and recrystallized from a mixed liquor of isopropyl alcohol and n-hexane to obtain 0.6 g. of a- (5-nitro-2-furyl -N- 1, l-dimethyl-2-dimethyl-aminoethyl) rlliltirt mtce3 (compound 55) as yellow needles melting at 114- EXAMPLE 56 To a solution of 2.76 g. of S-nitrofurfural and 6.14 g. of N-( l,1-dimethyl-2-piperidinoethyl)hydroxylamine hydrochloride in 20 ml. of ethanol was added 1.64 g. of anhydrous sodium acetate. The mixture was stirred for 6 hours at room temperature and for succeeding 4 hours at 65-70 C. The ethanol was removed by reduced pressure distillation. To the residue was added 20 ml. of 5% hydrochloric acid, and the resulting acidic solution was washed with ethanol and made alkaline with a saturated aqueous solution of sodium hydrogencarbonate. The precipitating crystals were collected by filtration, washed with water and recrystallized from a mixed liquor of ether and n-hexane to obtain 1.0 g. of a-(S-nitrO-Z-furyD-N- (l,1-dimethyl-Z-piperidinoethyl)nitrone (compound 56) as yellow prisms melting at 82-83 C.

EXAMPLE 57 To a solution of 1.41 g. of 5-nitrofurfural and 2.54 g. of N (1,1dimethyl-2-morpholinoethyl) hydroxylamine hydrochloride in 15 ml. of ethanol was added 1.64 g. of anhydrous sodium acetate, and the reaction was conducted at room temperature for 4 hours. To the reaction mixed liquor was added 50 ml. of water, and the precipitating crystals were collected by filtration, washed with water and recrystallized from isopropyl alcohol to obtain 0.7 g. of a (5-nitro-2-furyl)-N-(1,1-dimethyl-2- morpholinoethyl)nitrone (compound 57) as yellow needles melting at -12l C.

EXAMPLE 58 A solution of 2.12 g. of S-nitrofurfural and 3.28 g.

of N (2 isopropylamine-l,1-dimethylethyl)hydroxylamine hydrochloride in 15 ml. of ethanol was stirred for 1 3 EXAMPLE 63 The present example explains the excellent antimicrobial activities of the compound of the present invention on the basis of the results of in vivo experiments.

The Table II and Table III summarize in vivo activities of the compound against infection with Salmonella typhimurium and Trichomonas vaginalis in mice.

Infection with Salm nella typhimurium mice of each group were infected intraperitoneally 10 with 0.5 ml. of a bacterial suspension containing 1000 LD of Salmonella typhimurium. 12.5, 25 and 50 mg./kg. of a compound to be tested were administered orally twice a day for 4 days, the first treatment being made immediately after the infection. After 2 weeks observation, efficacy was expressed by survival rate (survived/tested).

The results are shown in Table II.

sisting of hydrogen, alkyl having 1 to 4 carbon atoms, halogen, hydroxyl, OM where M is an alkali metal, alkanoyloxy having 1 to 4 carbon atoms, benzoyloxy, salicoyloxy alkoxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms, alkanoylamino having 1 to 4 carbon atoms, carboxyl, alkali metal salt of carboxyl, alkoxy-carbonyl having 1 to 4 carbon atoms, carbamoyl, phenyl-substituted carbamoyl, alkyl-substituted carbamoyl wherein the alkyl has 1 to 4 carbon atoms, sulfamoyl, sulfoxyl, cyano and trifluoromethyl; m is an integer of 1 to 3; and q is an integer of 1 or 2.

2. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl)-N-methylnitrone.

3. The nitrone derivative of claim 1 wherein said derivative is u-(5-nitro-2-furyl)-N-ethylnitr0ne.

4. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitro-Z-furyl)-N-propy1nitrone.

TABLE II Compound No 1 2 3 6 6 7 8 33 46 Dose 50 mgJkg 10/10 7/10 5/10 9/10 10/10 8/10 10/10 10/10 8/10 mg./kg 8/10 1/10 8/10 10/10 6/10 8/10 10/10 12.5 Ing./kg 2/10 1/10 3/10 4/10 2/10 3/10 9/10 Non-treated control 0/10 Infection with Trichomonas vaginalis 5. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl)-N-isopropylnitrone.

6. The nitrone derivative of claim 1 wherein said derivative is u-(S-nitrO-Z-furyl N (l-methyl-Z-hydroxyethyl)nitrone.

7. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl)-N-(2-hydroxyethyl)nitrone.

8. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitrO-Z-furyU-N-[2-hydroxy-1-(hydroxymethyl )ethyl] nitrone.

TABLE III Compound No 1 2 3 4 5 6 7 8 10 13 16 33 46 55 57 59 Dose:

32552152212311: '1: if? 5? 3/5 3/5 3/5 2/5 3/5 3/5 3?? $2145.11? $2.14? Non-treated control 0/5 Mice having no viable protozoa/mice tested.

While the present invention has been described pri- 9. The nitrone derivative of Claim 1 wherein said marily with respect to the foregoing specific examples, it derivative is a-(5-nitro-2-furyl)-N-pheny1nitrone. is to be understood that the present invention is in no way 10. The nitrone derivative of claim 1 wherein said to be deemed as limited thereto. derivative is a-(5-nitro-2-furyl)-N-(4-methoxyphenyl)ni- We claim: t 1, A nit d iv ti f th f l 11. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl) N (B-methoxyphenyl) l i (I) rh d r 1 1 h d 12. e nitrone erivative o cairn w erein sai 02N o/-- CH I N R derivative is a-(S-nitro-Z-furyl)-N-(2-methoxyphenyl) H (I) nitrone. wherein n is 0 or I; R represents a member selected from 13, The nitrone derivativ of claim 1 wherein said the group consisting of A-X, A'(OH)mi )q and a derivative is a-(5-nitro-2-furyl) N (4-ethoxyphenyl)niheterocyclic radical selected from quinolyl, methoxy-subtrone, stitllted quinolyl, benzimidazolyl, benzotriazolyl and 14. The nitrone derivative of claim 1 wherein said zothiazolyl; wherein A and are each alkyl having 1 60 derivative is et- (5-nitro-2-furyl)-N-(4-tolyl)nitrone. t 6 car n atoms; P s p y X i a member selected 15. The nitrone derivative of claim 1 wherein said f the group consisting of y g p y g derivative is a- (5-nitro-2-furyl)-N-(3-trifluoromethylalkoxy of 1 to 4 carbon atoms; alkoxy-carbonyl in which h 1) i the alkoxy Portion has 1 to 4 carbon atoms, carbamoyl, 16. The nitrone derivative of claim 1 wherein said Ilitfo, sulfoxyl, alkali metal oxysulfonyl, py y and an 5 derivative is u-(5-nitro 2- furyl)-N-(4-chlorophenyl) amino radical of the formula it 17. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitro-Z-furyD-N-(3,4-dichlorophenyl) nitrone.

R! (H) 18. The nitrone derivative of claim 1 wherein said in which R and R each are a member selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, and phenyl, or R and R may together with the nitrogen atom of said amino be piperidino and morpholino; Y is a member selected from the group conderivative is a-(5-nitro 2 furyl)-N-(4-iodophenyl) nitrone.

19. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitro-Z-furyl)-N-(4-carboxyphenyl) nitrone.

20. The nitrone derivative of claim 1 wherein said derivative is a-(-nitro-2-furyl)-N-(3-carboxyphenyl) nitrone.

2-1. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitro 2 furyl)'-N-(Z-carboxyphenyl) nitrone.

22. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl)-N-(4-methoxycarbonylphenyl)nitrone.

23. The nitrone derivative of claim 1 wherein said derivative is a- (S-nitro-Z-furyl)-N-(4-carbamoylphenyl) nitrone.

24. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro 2 furyl)-N-(4-cyanophenyl) nitrone.

25. The nitrone derivative of claim 1 wherein said derivative is a-*(5-nitro-2-furyl)-N-(4-sulfarnoylphenyl) nitrone.

2.6. The nitrone derivative of claim 1 wherein said derivative is a-(S-nitro-Z-furyl)-N-(5-benzimidaz0lyl) nitrone.

27. The nitrone derivative of claimv 1 wherein said derivative is a-(S-nitro-Z-furyD-N-(6-quinolyl)nitrone.

28. The nitronev derivative of claim 1 wherein said derivative is a-(S-nitro-Z-furyl)-N-(4-sodioxycarbonylphenyl) nitrone.

29. The nitrone derivative of claim 1 wherein said derivative is a-(nitro-2-furyl)-N-(4-salicyloyloxyphenyl) nitrone.

30. The nitrone derivatives of claim 1 wherein said derivative is a-(S-nitro-Z-furyl)-N-(5-benz0triazolyl) nitrone.

31. The nitrone derivative of claim 1 wherein said derivative is a [2-(S-nitro-Z-furyDvinyl]-N-methylnitrone.

32. The nitrone derivative of claim 1 wherein said derivative is a-[2-(5-nitro-2-furyl)vinyl]-N-(3-carboxyphenyl)nitrone.

33. The nitrone derivative of claim 1 wherein said derivative is a-[Z-(5-nitro-2-furyl)vinyl]-N-(l-hydroxymethylethyl)nitrone.

34. The nitrone derivative of claim 1 wherein said derivative is tic-[2-(5-nitro-2-furyl)vinyl]-N-(2-hydroxyethyl)nitrone.

16 35. The nitrone derivative of claim 1 wherein said derivative is a- [2- (S-nitro-Z-furyl vinyl] -N- (4-sulfamoylphenyl)nitrone.

36. The nitrone derivative of claim 1 wherein said derivative is a- [2- (5-nitro-2-furyl vinyl] -N-6-quinoyl) nitrone.

37. The nitrone derivative of claim 1 wherein said derivative is a-(5-nitro-2-furyl)-N-(1,1-dimethyl-2-diwherein R is hydrogen or alkyl of 1 to 4 carbon atoms and A is alkyl of 1 to 6 carbon atoms.

References Cited FOREIGN PATENTS 952,895 11/1956 Germany 260-240 G ALEX MAZEL, Primary Examiner B. DENTZ, Assistant Examiner US. Cl. X.R. 

